Kinetics and metabolism of (+)-, (?)- and (�)-bufuralol

Francis, Robert J.; East, P. B.; Larman, J.

doi:10.1007/bf00637501

Cited by 34 publications

(19 citation statements)

References 11 publications

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“…(ϩ/Ϫ)-Bufuralol is a nonselective ␤-adrenoceptor blocking agent; its major metabolic pathways in humans are oxidation and glucuronidation [16,17], and our recent study showed that there are seven major metabolic pathways in vitro [6]. Predictive multiple reaction monitoring (MRM) is the most sensitive approach in metabolite identification [18,19].…”

Section: Metabolite Identification and Validation In Hihsmentioning

confidence: 99%

Highly Efficient Differentiation of Functional Hepatocytes From Human Induced Pluripotent Stem Cells

Duan

Tschudy-Seney

et al. 2013

Stem Cells Translational Medicine

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Human induced pluripotent stem cells (hiPSCs) hold great potential for use in regenerative medicine, novel drug development, and disease progression/developmental studies. Here, we report highly efficient differentiation of hiPSCs toward a relatively homogeneous population of functional hepatocytes. hiPSC-derived hepatocytes (hiHs) not only showed a high expression of hepatocyte-specific proteins and liver-specific functions, but they also developed a functional biotransformation system including phase I and II metabolizing enzymes and phase III transporters. Nuclear receptors, which are critical for regulating the expression of metabolizing enzymes, were also expressed in hiHs. hiHs also responded to different compounds/inducers of cytochrome P450 as mature hepatocytes do. To follow up on this observation, we analyzed the drug metabolizing capacity of hiHs in real time using a novel ultraperformance liquid chromatography-tandem mass spectrometry. We found that, like freshly isolated primary human hepatocytes, the seven major metabolic pathways of the drug bufuralol were found in hiHs. In addition, transplanted hiHs engrafted, integrated, and proliferated in livers of an immune-deficient mouse model, and secreted human albumin, indicating that hiHs also function in vivo. In conclusion, we have generated a method for the efficient generation of hepatocytes from induced pluripotent stem cells in vitro and in vivo, and it appears that the cells function similarly to primary human hepatocytes, including developing a complete metabolic function. These results represent a significant step toward using patient/disease-specific hepatocytes for cell-based therapeutics as well as for pharmacology and toxicology studies. STEM CELLS TRANS- LATIONAL MEDICINE 2013;2:409 -419

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Section: Metabolite Identification and Validation In Hihsmentioning

confidence: 99%

Highly Efficient Differentiation of Functional Hepatocytes From Human Induced Pluripotent Stem Cells

Duan

Tschudy-Seney

et al. 2013

Stem Cells Translational Medicine

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“…Bufuralol is a chiral adrenoceptor antagonist that undergoes extensive oxidative metabolism in humans (Francis et al, 1982;Dayer et al, 1983Dayer et al, , 1986, where the aliphatic…”

Section: Cyp1a2mentioning

confidence: 99%

Evaluation of Cytochrome P450 Probe Substrates Commonly Used by the Pharmaceutical Industry to Study in Vitro Drug Interactions

Yuan

Madani²,

Wei³

et al. 2002

Drug Metab Dispos

295

191

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ABSTRACT:Pharmaceutical industry investigators routinely evaluate the potential for a new drug to modify cytochrome P450 (P450) activities by determining the effect of the drug on in vitro probe reactions that represent activity of specific P450 enzymes. The in vitro findings obtained with one probe substrate are usually extrapolated to the compound's potential to affect all substrates of the same enzyme. Due to this practice, it is important to use the right probe substrate and to conduct the experiment under optimal conditions. Surveys conducted by reviewers in CDER indicated that the most common in vitro probe reactions used by industry investigators include the following: phenacetin O-deethylation for CYP1A2, coumarin 7-hydroxylation for CYP2A6, 7-ethoxy-4-trifluoromethyl coumarin O-dealkylation for CYP2B6, tolbutamide 4-hydroxylation for CYP2C9, S-mephenytoin 4-hydroxylation for CYP2C19, bufuralol 1-hydroxylation for CYP2D6, chlorzoxazone 6-hydroxylation for CYP2E1, and testosterone 6␤-hydroxylation for CYP3A4. We reviewed the validation information in the literature on these reactions and other frequently used reactions, including caffeine N3-demethylation for CYP1A2, S-mephenytoin N-demethylation for CYP2B6, S-warfarin 7-hydroxylation for CYP2C9, dextromethorphan O-demethylation for CYP2D6, and midazolam 1-hydroxylation for CYP3A4. The available information indicates that we need to continue the search for better probe substrates for some enzymes. For CYP3A4-based drug interactions it may be necessary to evaluate two or more probe substrates. In many cases, the probe reaction represents a particular enzyme activity only under specific experimental conditions. Investigators must consider appropriateness of probe substrates and experimental conditions when conducting in vitro drug interaction studies and when extrapolating the results to in vivo situations.During the drug-candidate screening and development process, investigators often conduct two types of in vitro drug metabolism studies to assess the potential for P450 1 -based drug interactions. One type of study characterizes the metabolic pathway of the new drug and the potential for other drugs to modify the metabolism of the new drug. The other type of study evaluates the potential for the new drug to alter the metabolism of other drugs. Due to the availability of antibodies against specific P450 enzymes, cDNA-expressed enzymes, purified enzymes, and selective chemical inhibitors, the unequivocal identification of the major P450 isoform responsible for the metabolism of a new drug can be easily established. However, predicting the potential for the new drug to alter the metabolism of other drugs usually relies on the evaluation of the effect of the new drug on the rate of a probe reaction that represents a specific P450 enzyme activity. The second type of evaluation is more challenging and is the focus of this review.

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“…The β-blocking potency of (1S)-bufuralol is approximately 100 times greater than that of the (1R)-enantiomer. 4 The metabolism of bufuralol is complex; many metabolites are formed, 5 differential metabolism between the two enantiomers occurs, 6 and differences due to genetic polymorphism are also encountered. 7 Nevertheless, the metabolites, diastereomeric carbinols and enatiomeric ketones, both of which are present to a large extent in a biological fluid, also have pharmacological activity 8 comparable to the parent drug.…”

mentioning

confidence: 99%

Production and Characterization of Monoclonal Antibodies Recognizing the Asymmetric Center of Optically Active Bufuralol and Its Metabolites

et al. 2000

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The chromatographic determination of enantiomeric drugs and the metabolites in biological fluids is one of the most important subjects in biomedical analysis, because the individual isomers exhibit different pharmacological properties as well as pharmacokinetic and metabolic fates.Bufuralol, 1-(7-ethylbenzofuran-2-yl)-2-t-butylamino-1-hydroxyethane, is a nonselective β-adrenergic receptor antagonist 1 with partial β2-agonist properties 2,3 and is administered as the racemic form. The β-blocking potency of (1S)-bufuralol is approximately 100 times greater than that of the (1R)-enantiomer. 4 The metabolism of bufuralol is complex; many metabolites are formed, 5 differential metabolism between the two enantiomers occurs, 6 and differences due to genetic polymorphism are also encountered. 7 Nevertheless, the metabolites, diastereomeric carbinols and enatiomeric ketones, both of which are present to a large extent in a biological fluid, also have pharmacological activity 8 comparable to the parent drug. Therefore, a reliable method for the simultaneous determination of enantiomeric bufuralol along with its metabolites is essential for pharmacokinetic and pharmacodynamic studies.Various chromatographic methods are now available for the separation and determination of enantiomers. The analytical procedure includes the use of a chiral chromatographic mode based on either chiral stationary phases or chiral eluents, and the use of a derivatization technique with a chiral reagent to produce the diastereomers, which are easily separated with a conventional separation column. [9][10][11][12][13] There are a number of chiral reagents having a reacting group to form a covalent bond with target analytes and a signal group highly responsive to a detector. 14 The reaction should proceed completely without any racemization. This method, although it is favorable for obtaining higher sensitivity, has disadvantages due to the tedious derivatization process and a clean-up procedure to remove excess reagents. Moreover, it has been shown that enantiomers can react with a chiral reagent at very different rates. 15High-performance liquid chromatography (HPLC) employing chiral stationary phases is well recognized as a powerful tool for the direct separation of racemates. A wide variety of separation columns including the Pirkle-type, cyclodextrin-bonded, various cellulose-based, and immobilized protein columns have been developed and are commercially available.In recent years, immunoaffinity chromatography (IAC) based on specific and reversible antigen-antibody reactions 16 has been shown to be capable of separating and determining a number of different analytes and to be a powerful analytical or pretreatment tool in biomedical analysis. In our previous study, rabbit polyclonal antibodies with high specificity for an essential chirality center have been prepared for the enantiomeric immunoaffinity extraction of optically active bufuralol and its 1′-oxidized metabolites. 17 However, it is difficult to obtain conventional polyclonal antibodi...

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Kinetics and metabolism of (+)-, (?)- and (�)-bufuralol

Cited by 34 publications

References 11 publications

Highly Efficient Differentiation of Functional Hepatocytes From Human Induced Pluripotent Stem Cells

Highly Efficient Differentiation of Functional Hepatocytes From Human Induced Pluripotent Stem Cells

Evaluation of Cytochrome P450 Probe Substrates Commonly Used by the Pharmaceutical Industry to Study in Vitro Drug Interactions

Production and Characterization of Monoclonal Antibodies Recognizing the Asymmetric Center of Optically Active Bufuralol and Its Metabolites

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